EP3960181A2 - Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose - Google Patents

Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose Download PDF

Info

Publication number
EP3960181A2
EP3960181A2 EP21198646.8A EP21198646A EP3960181A2 EP 3960181 A2 EP3960181 A2 EP 3960181A2 EP 21198646 A EP21198646 A EP 21198646A EP 3960181 A2 EP3960181 A2 EP 3960181A2
Authority
EP
European Patent Office
Prior art keywords
fibrosis
therapeutic
pharmaceutical composition
disease
yap
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP21198646.8A
Other languages
English (en)
French (fr)
Other versions
EP3960181A3 (de
Inventor
James Allen CARDELLI
Charles Albert STEPHENS
Alana Lea GRAY
David Thomas COLEMAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Louisiana State University and Agricultural and Mechanical College
Original Assignee
Louisiana State University and Agricultural and Mechanical College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Louisiana State University and Agricultural and Mechanical College filed Critical Louisiana State University and Agricultural and Mechanical College
Publication of EP3960181A2 publication Critical patent/EP3960181A2/de
Publication of EP3960181A3 publication Critical patent/EP3960181A3/de
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • This invention generally relates to the screen and identification of drugs and use of these drugs for the treatment of invasive cancer and fibrotic diseases, and treatments for activated fibroblast associated diseases, including, but not limited to, treatments that target cancer associated fibroblasts.
  • Fibroblasts play an important role in the development and progression of tumors as well as in fibrotic diseases such as pulmonary fibrosis, scleroderma, chronic kidney disease, and at least some cancers, just for example.
  • Current medications to treat activated fibroblast associated diseases are inadequate in efficacy and some are toxic to the patient.
  • tumor progression is accompanied by the activation of stromal fibroblasts into myofibroblasts often termed cancer-associated fibroblasts (CAFs).
  • CAFs cancer-associated fibroblasts
  • CAFs can induce invasion of tumor cells leading to metastasis.
  • Inhibition of CAFs combined with therapies that target tumors is believed to advance cancer treatments by, in the least, preventing the CAF induced invasion of tumor cells leading to metastasis.
  • CAFs Tumor cells progress to invasion and metastasis in part due to communication with cells known as CAFs. This is especially prevalent in cancers such as pancreatic cancer where the five year survival rate is less than 5 percent.
  • No accepted therapies are available that target these stromal cells.
  • Another target is fibrotic diseases of the lung, kidney and other organs are due to over activated fibroblasts.
  • Presently only two recent drugs with unknown long term effects therapeutic options are available for such fibrotic diseases.
  • the inventors utilized a high content imaging approach to screen the Prestwick repurposed drug library containing 1280 drugs. This screen yielded 19 drugs that blocked induction of fibronectin, a marker for CAFs.
  • the invention further relates to methods and therapeutic products including a first pharmaceutically active agent being one of an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, and a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, or a combination thereof; and a further pharmaceutically active agent.
  • a first pharmaceutically active agent being one of an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, and a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, or a combination thereof; and a further pharmaceutically active agent.
  • the further pharmaceutically active agent is one or more additional intracellular Ca 2+ elevators, including cardiac glycosides, YAP/TAZ inhibitors, and/or chemicals listed in Tables 1 and 2, or a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, distinct from the first pharmaceutically active agent.
  • the further pharmaceutically active agent is one or more receptor tyrosine kinase inhibitors; a receptor tyrosine kinase inhibited is one of c-Met, RON, ROS, EGFR1, EGFR2, EGFR3, EGFR4, EGRFvIII, c-Kit, c-FMS, FLT3, PDGFR, IGFR, VEGFR, VEGR2, TIE-1, TIE-2, PTK-7, FGFR1-3, TRKA-C, RORs, BCR-ABL, EPHA1-5, EPHB1-4, and RET; and the receptor tyrosine kinase inhibitor is one of Alectinib, Axitinib, Crizotinib, Cabozantinib, Centinib, Erlotinib, Gefitinib, Lapatinib, Lenvatinib, Osimertinib, Pazopanib, Ponatinib, Regora
  • the further pharmaceutically active agent is one or more agents that target non-receptor tyrosine kinases;
  • the non-receptor tyrosine kinase is one of ABL1-2, ACK1, BLK, Bmx, bRAF, BRK, BTK, CSK, FAK, FES, FRK, FYNA, HCK, ITK, Jak1-2, LCK, Lok1, LRRK2, LYNA-B, MNK1,MEK, mTOR, PI3K, PYK2, Src, Syk, Zap-70, and CDK4;
  • the agent that targets the non-receptor tyrosine kinase is one of Bosultinib, Cobimetinib, Dabrafenib, Dasatinib, Everolimus, Ibrutinib, Idelalisib, Imatinib, nilotinib, Palbociclib, Ponatinib, Rogorafen
  • the further pharmaceutically active agent is one or more anti-cell proliferative chemotherapeutic agent and the anti-cell proliferative chemotherapeutic agent is one of an anti-cancer and anti-tumor drug; an alkylating agent, anti-metabolite, plant extract, plant alkaloid, nitrosourea, hormone, nucleoside analog, and nucleotide analog; and 5-fluorouracil, cyclophosphamide, azathioprine, cyclosporin A, prednisolone, melphalan, chlorambucil, mechlorethamine, busulphan, methotrexate, 6-mercaptopurine, thioguanine, cytosine arabinoside, AZT, 5-azacytidine (5-AZC), bleomycin, actinomycin D, mithramycin, mitomycin C, carmustine, lomustine, semustine, streptozotocin, hydroxyurea, cis
  • active agent includes an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2 as described herein.
  • active agent may also be referred to as the active compound, active ingredient, active material, the inventive compound and/or the active drug substance.
  • delayed release includes a pharmaceutical preparation, e.g., an orally administered formulation, which passes through the stomach substantially intact and dissolves in the small and/or large intestine (e.g., the colon).
  • delayed release of the active results from the use of an enteric coating of an oral medication (e.g., an oral dosage form).
  • an "effective amount” of an agent includes that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied.
  • extended release or “sustained release” interchangeably includes a drug formulation that provides for gradual release of a drug over an extended period of time, e.g., 6-12 hours or more, compared to an immediate release formulation of the same drug.
  • extended release results in substantially constant blood levels of a drug over an extended time period that are within therapeutic levels and fall within a peak plasma concentration range that is between, for example, 0.05-10 ⁇ M, 0.1-10 ⁇ M, 0.1-5.0 ⁇ M, or 0.1-1 ⁇ M.
  • the terms "formulated for enteric release” and "enteric formulation” include pharmaceutical compositions, e.g., oral dosage forms, for oral administration able to provide protection from dissolution in the high acid (low pH) environment of the stomach.
  • Enteric formulations can be obtained by, for example, incorporating into the pharmaceutical composition a polymer resistant to dissolution in gastric juices.
  • the polymers have an optimum pH for dissolution in the range of approx. 5.0 to 7.0 ("pH sensitive polymers").
  • Exemplary polymers include methacrylate acid copolymers that are known by the trade name Eudragit ® (e.g., Eudragit ® L100, Eudragit ® S100, Eudragit ® L-30D, Eudragit ® FS 30D, and Eudragit ® L100-55), cellulose acetate phthalate, cellulose acetate trimellitiate, polyvinyl acetate phthalate (e.g., Coateric ® ), hydroxyethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, or shellac, or an aqueous dispersion thereof.
  • Eudragit ® e.g., Eudragit ® L100, Eudragit ® S100, Eudragit ® L-30D, Eudragit ® FS 30D, and Eudragit ® L100-55
  • cellulose acetate phthalate e.g., cellulose acetate trimellitiate
  • Aqueous dispersions of these polymers include dispersions of cellulose acetate phthalate (Aquateric ® ) or shellac (e.g., MarCoat 125 and 125N).
  • An enteric formulation reduces the percentage of the administered dose released into the stomach by at least 50%, 60%, 70%, 80%, 90%, 95%, or even 98% in comparison to an immediate release formulation. Where such a polymer coats a tablet or capsule, this coat is also referred to as an "enteric coating.”
  • immediate release includes that the agent (e.g., an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof), as formulated in a unit dosage form, has a dissolution release profile under in vitro conditions in which at least 55%, 65%, 75%, 85%, or 95% of the agent is released within the first two hours of administration to, e.g., a human.
  • the agent e.g., an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof
  • the agent formulated in a unit dosage has a dissolution release profile under in vitro conditions in which at least 50%, 65%, 75%, 85%, 90%, or 95% of the agent is released within the first 30 minutes, 45 minutes, or 60 minutes of administration.
  • composition includes a composition containing an active agent described herein (e.g., an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof), formulated with a pharmaceutically acceptable excipient, and typically manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal, especially with the mammal being a human..
  • an active agent described herein e.g., an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • a "pharmaceutically acceptable excipient,” as used herein, includes an ingredient other than the active agents described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, maltose, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc,
  • prodrugs as used herein, includes those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts include those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic or inorganic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • solvates includes a compound of the invention wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the administered dose.
  • solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof.
  • Suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N'- dimethylformamide (DMF), N , N '-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like.
  • NMP N-methylpyrrolidinone
  • DMSO dimethyl sulfoxide
  • DMF N n'- dimethylformamide
  • DMAC 1,3-dimethyl-2-imidazolidinone
  • DMPU 1,3-dimethyl-3,4,5,6-tetrahydr
  • prevent includes prophylactic treatment or treatment that prevents one or more symptoms or conditions of a disease, disorder, or conditions described herein (e.g., activated fibroblast associated disease or pre-disease state), or may refer to a treatment of a pre-disease state.
  • Treatment can be initiated, for example, prior to ("pre-exposure prophylaxis") or following ("post-exposure prophylaxis") an event that precedes the onset of the disease, disorder, or conditions.
  • Treatment that includes administration of a compound of the invention, or a pharmaceutical composition thereof can be acute, short-term, or chronic. The doses administered may be varied during the course of preventive treatment.
  • prodrug includes compounds which are rapidly transformed in vivo to the parent compound of the above formula.
  • Prodrugs also encompass bioequivalent compounds that, when administered to a human, lead to the in vivo formation of an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof.
  • treatment includes an approach for obtaining beneficial or desired results, such as clinical results.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e. not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the terms “treating” and “treatment” can also refer to delaying the onset of, impeding or reversing the progress of, or alleviating either the disease or condition to which the term applies, or one or more symptoms of such disease or condition.
  • unit dosage forms includes physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with any suitable pharmaceutical excipient or excipients.
  • the present compounds can be prepared from readily available starting materials using the methods and procedures known in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.
  • compositions can also include the administrations of pharmaceutically acceptable compositions that include intracellular Ca 2+ elevators, including cardiac glycosides, YAP/TAZ inhibitors, and/or chemicals listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof.
  • Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated so that a given pharmaceutical composition or dosage form inhibits activated fibroblast associated disease or pre-disease state cell proliferation or other disease or condition where inhibiting the hepatocyte growth factor receptor can therapeutically influence the respective disease or condition progression.
  • compositions and dosage forms comprise an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof, optionally in combination with one or more additional active agents.
  • any of the present active agents can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration may be topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, by suppositories, or oral administration.
  • compositions which can contain one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules.
  • the type of diluent can vary depending upon the intended route of administration.
  • the resulting compositions can include additional agents, such as preservatives.
  • the therapeutic agents of the invention e.g., an intracellular Ca 2+ elevator, including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof
  • an intracellular Ca 2+ elevator including cardiac glycosides, a YAP/TAZ inhibitor, and/or a chemical listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof
  • the excipient or carrier is selected on the basis of the mode and route of administration.
  • Suitable pharmaceutical carriers as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005 ), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary).
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents wetting agents
  • emulsifying and suspending agents preserving agents such as methyl- and propylhydroxybenzoates
  • sweetening agents and flavoring agents.
  • Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Row
  • compositions can be formulated so as to provide immediate, extended, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the pharmaceutical compositions can be formulated in a unit dosage form, each dosage containing, e.g., 0.1-500 mg of the active ingredient.
  • the dosages can contain from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.2 mg to about 20 mg, from about 0.3 mg to about 15 mg, from about 0.4 mg to about 10 mg, from about 0.5 mg to about 1 mg; from about 0.5 mg to about 100 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 30 mg,, from about 0.5 mg to about 20 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 5 mg; from about 1 mg from to about 50 mg, from about 1 mg to about 30 mg,, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg; from about 5 mg to about 50 mg, from about 1 mg to about 30 mg, from about 1 mg to
  • the active agent may be mixed with one or more pharmaceutical excipients to form a solid bulk formulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid bulk formulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets and capsules.
  • This solid bulk formulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • compositions for Oral Administration include those formulated for oral administration ("oral dosage forms").
  • Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiad
  • Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Controlled release compositions for oral use may be constructed to release the active agent by controlling the dissolution and/or the diffusion of the active agent substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration vs time profile.
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the administered therapeutic or drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • compositions include biodegradable, pH, and/or temperature-sensitive polymer coatings.
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions suitable for oral mucosal administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • the pharmaceutical compositions formulated for oral delivery can be coated or otherwise compounded to provide a dosage form affording the advantage of delayed or extended release.
  • the coating may be adapted to release the active agent in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active agent until after passage of the stomach, e.g., by use of an enteric coating (e.g., polymers that are pH-sensitive (“pH controlled release”), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion (“time-controlled release”), polymers that are degraded by enzymes (“enzyme-controlled release” or “biodegradable release”) and polymers that form firm layers that are destroyed by an increase in pressure (“pressure-controlled release”)).
  • enteric coating e.g., polymers that are pH-sensitive (“pH controlled release"), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion (“time-controlled release"), polymers that are degraded by enzymes (“
  • Exemplary enteric coatings that can be used in the pharmaceutical compositions described herein include sugar coatings, film coatings (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or coatings based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose.
  • a time delay material such as, for example, glyceryl monostearate or glyceryl distearate, may be employed.
  • the tablet or capsule can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • an enteric coating desirably, a substantial amount of the active agent is released in the lower gastrointestinal tract.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes (e.g., chemical degradation prior to the release of the active agent).
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, vols. 5 and 6, Eds. Swarbrick and Boyland, 2000 .
  • parenteral depot systems from biodegradable polymers. These systems are injected or implanted into the muscle or subcutaneous tissue and release the incorporated active agent over extended periods of time, ranging from several days to several months. Both the characteristics of the polymer and the structure of the device can control the release kinetics which can be either continuous or pulsatile.
  • Polymer-based parenteral depot systems can be classified as implants or microparticles. The former are cylindrical devices injected into the subcutaneous tissue whereas the latter are defined as spherical particles in the range of 10 - 100 ⁇ m.
  • Extrusion, compression or injection molding are used to manufacture implants whereas for microparticles, the phase separation method, the spray-drying technique and the water-in-oil-in-water emulsion techniques are frequently employed.
  • the most commonly used biodegradable polymers to form microparticles are polyesters from lactic and/or glycolic acid, e.g. poly(glycolic acid) and poly(L-lactic acid) (PLG/PLA microspheres).
  • PLA/PLA microspheres poly(L-lactic acid)
  • in situ forming depot systems such as thermoplastic pastes and gelling systems formed by solidification, by cooling, or due to the sol-gel transition, cross-linking systems and organogels formed by amphiphilic lipids.
  • thermosensitive polymers used in the aforementioned systems include, N-isopropylacrylamide, poloxamers (ethylene oxide and propylene oxide block copolymers, such as poloxamer 188 and 407), poly(N-vinyl caprolactam), poly(siloethylene glycol), polyphosphazenes derivatives and PLGA-PEG-PLGA.
  • Mucosal drug delivery e.g., drug delivery via the mucosal linings of the nasal, rectal, vaginal, ocular, or oral cavities
  • Methods for oral mucosal drug delivery include sublingual administration (via mucosal membranes lining the floor of the mouth), buccal administration (via mucosal membranes lining the cheeks), and local delivery ( Harris et al., Journal of Pharmaceutical Sciences, 81(1): 1-10, 1992 )
  • Oral transmucosal absorption is generally rapid because of the rich vascular supply to the mucosa and allows for a rapid rise in blood concentrations of the therapeutic or active agent (" American Academy of Pediatrics: Alternative Routes of Drug Administration---Advantages and Disadvantages (Subject Review),” Pediatrics, 100(1):143-152, 1997 ).
  • compositions may take the form of, e.g., tablets, lozenges, etc. formulated in a conventional manner.
  • Permeation enhancers can also be used in buccal drug delivery.
  • Exemplary enhancers include 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, lysophosphatidylcholine, methol, methoxysalicylate, methyloleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, and alkyl glycosides.
  • Bioadhesive polymers have extensively been employed in buccal drug delivery systems and include cyanoacrylate, polyacrylic acid, hydroxypropyl methylcellulose, and poly methacrylate polymers, as well as hyaluronic acid and chitosan.
  • Liquid drug formulations e.g., suitable for use with nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices
  • EHD electrohydrodynamic
  • Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art.
  • Formulations for sublingual administration can also be used, including powders and aerosol formulations.
  • Exemplary formulations include rapidly disintegrating tablets and liquid-filled soft gelatin capsules.
  • Dosing Regimens The present methods for treating activated fibroblast associated disease or pre-disease state are carried out by administering one or more intracellular Ca 2+ elevators, including cardiac glycosides, YAP/TAZ inhibitors, and/or chemicals listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug, or analog thereof, or a combination thereof for a time and in an amount sufficient to result in stabilization and /or reversal of activated fibroblast associated disease or pre-disease state symptoms, or other disease or condition where inhibiting the hepatocyte growth factor receptor can therapeutically influence the respective disease or condition progression.
  • intracellular Ca 2+ elevators including cardiac glycosides, YAP/TAZ inhibitors, and/or chemicals listed in Tables 1 and 2, or any pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer,
  • the amount and frequency of administration of the compositions can vary depending on, for example, what is being administered, the state of the patient, and the manner of administration.
  • the dosage is likely to depend on such variables as the type and extent of progression of the activated fibroblast associated disease or pre-disease state, the severity of the activated fibroblast associated disease or pre-disease state, the age, weight and general condition of the particular patient, the relative biological efficacy of the composition selected, formulation of the excipient, the route of administration, and the judgment of the attending clinician.
  • Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test system.
  • An effective dose is a dose that produces a desirable clinical outcome by, for example, improving a sign or symptom of activated fibroblast associated disease or pre-disease state or slowing its progression.
  • the amount of active agent per dose can vary.
  • a subject can receive from about 0.1 ⁇ g/kg to about 50,000 ⁇ g/kg.
  • the active agent is administered in an amount such that the peak plasma concentration ranges from 1.50 nM-250 ⁇ M.
  • Exemplary dosage amounts can fall between 0.1-5000 ⁇ g/kg, 100-1500 ⁇ g/kg, 100-350 ⁇ g/kg, 340-750 ⁇ g/kg, or 750-1000 ⁇ g/kg. Exemplary dosages can 0.25, 0.5, 0.75, 1.0, or 2.0 mg/kg. In another embodiment, the administered dosage can range from 0.05-5 mmol of an active agent (e.g., 0.089-3.9 mmol) or 0.1-50 ⁇ mol of an active agent (e.g., 0.1-25 ⁇ mol or 0.4-20 ⁇ mol).
  • an active agent e.g., 0.089-3.9 mmol
  • 0.1-50 ⁇ mol of an active agent e.g., 0.1-25 ⁇ mol or 0.4-20 ⁇ mol.
  • the frequency of treatment may also vary.
  • the subject can be treated one or more times per day with the active agent (e.g., once, twice, three, four or more times) or every so-many hours (e.g., about every 2, 4, 6, 8, 12, or 24 hours).
  • the pharmaceutical composition is administered 1 or 2 times per 24 hours.
  • the time course of treatment may be of varying duration, e.g., for two, three, four, five, six, seven, eight, nine, ten or more days.
  • the treatment can be twice a day for three days, twice a day for seven days, twice a day for ten days.
  • Treatment cycles can be repeated at intervals, for example weekly, bimonthly or monthly, which are separated by periods in which no treatment is given.
  • the treatment can be a single treatment or can last as long as the life span of the subject (e.g., many years).
  • Kit may include instructions for use of the pharmaceutical compositions as a therapy as described herein.
  • the instructions may provide dosing and therapeutic regimes for use of the compounds of the invention to reduce incidence, duration, and or severity of activated fibroblast associated disease or pre-disease state.
  • the disclosed invention relates to products and methods of treating an activated fibroblast associated disease or pre-disease condition in a mammal comprising administering a pharmaceutical composition including a therapeutically effective amount of a first therapeutic; wherein the first therapeutic is one of an intracellular Ca 2+ elevator, a YAP / TAZ inhibitor, both a intracellular Ca 2+ elevator and a YAP / TAZ inhibitor, or pharmacologically acceptable salts, solvates, esters, amides, clathrates, stereoisomers, enantiomers, prodrugs or analogs thereof, or a combination thereof.
  • the first therapeutic includes an intracellular Ca 2+ elevator or a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, or a combination thereof.
  • the intracellular Ca 2+ elevator inhibits sodium-potassium ATPase.
  • the intracellular Ca 2+ elevator is a cardiaoglycoside.
  • the intracellular Ca 2+ elevator is selected from a group comprising menthol, linalool (3,7-dimethylocta-1,6-dien-3-ol), geraniol ((trans)- 3,7-Dimethyl-2,6-octadien-1-ol), hydroxy-citronellal (7-hydroxy-3,7-dimethyloctanal), WS-3 (N-ethyl-5-methyl-2-propan-2-ylcyclohexane-1 - carboxamide), WS-23 (N,2,3-trimethyl-2-propan-2-ylbutanamide), Frescolat MGA ((9-methyl-6-propan-2-yl-1,4-dioxaspiro[4.5]decan-2-yl)methanol), Frescolat ML ([(1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexyl] 2-hydroxypropanoate), PMD 38
  • the first therapeutic includes a YAP / TAZ inhibitor or a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, or a combination thereof.
  • the YAP/TAZ inhibitor is one of ⁇ E-catenin, thiazovivin, cucurbitacin I, dasatinib, fluvastatin, pazopanib, a statin, and pyrvinium.
  • the YAP/TAZ inhibitor is pyrvinium prepared with a variable counter anion including one of a halide, tosylate, triflate and pamoate.
  • the pharmaceutical composition further includes a therapeutically effective amount of a second therapeutic, wherein the second therapeutic is chemically distinct from the first therapeutic.
  • the second therapeutic is one of an intracellular Ca 2+ elevator, a YAP / TAZ inhibitor, both a intracellular Ca 2+ elevator and a YAP / TAZ inhibitor, or pharmacologically acceptable salts, solvates, esters, amides, clathrates, stereoisomers, enantiomers, prodrugs or analogs thereof, or a combination thereof.
  • the second therapeutic is one of gemcitabine, Nab-paclitaxel, and both gemcitabine and Nab-paclitaxel.
  • the second therapeutic is one of nintedanib, pirfenidone, and both nintedanib and pirfenidone.
  • the second therapeutic is one of a cardioglycoside, an intracellular Ca 2+ elevator, a sodium-potassium ATPase inhibitor, an anti-cancer chemical, a protein synthesis inhibitor, an antimicrobial, an anti-parasitic, YAP/TAZ inhibitor, a macrolide antibiotic, an anthracycline antibiotic, a topoisomerease inhibitor, a diterpenoid epoxide, a tryptamin, and an antiarythmic.
  • the activated fibroblast associated disease or pre-disease condition is one of fibrosis, pulmonary fibrosis, Cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, cardiac fibrosis, atrial fibrosis, endomycocardial fibrosis, old myocardial fibriosis, glial scarring (gliosis), renal fibrosis, pancreatic cancer, arthrofibrosis, crohn's disease, dupuytren's contracture, myofibroblastic tumors, mediastinal fibrosis, retroperitoneal cavity fibrosis, myelofibrosis, keloid/skin fibrosis, pyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis,
  • the activated fibroblast associated disease or pre-disease condition is a type of cancer. According to a further embodiment the activated fibroblast associated disease or pre-disease condition is a non-cancer disease. According to a further embodiment the mammal is a human. According to a further embodiment the first therapeutic is administered in a microMolar concentration.
  • the disclosed invention further relates to products and methods of treating an activated fibroblast associated disease or pre-disease condition in a mammal comprising administering a pharmaceutical composition including a therapeutically effective amount of a first therapeutic, wherein the first therapeutic is one of a cardioglycoside, an intracellular Ca 2+ elevator, a sodium-potassium ATPase inhibitor, an anti-cancer chemical, a protein synthesis inhibitor, an antimicrobial, an anti-parasitic, YAP/TAZ inhibitor, a macrolide antibiotic, an anthracycline antibiotic, a topoisomerease inhibitor, a diterpenoid epoxide, a tryptamin, and an antiarythmic.
  • a pharmaceutical composition including a therapeutically effective amount of a first therapeutic, wherein the first therapeutic is one of a cardioglycoside, an intracellular Ca 2+ elevator, a sodium-potassium ATPase inhibitor, an anti-cancer chemical, a protein synthesis inhibitor, an
  • the pharmaceutical composition further includes a therapeutically effective amount of a second therapeutic
  • the second therapeutic is one of a cardioglycoside, an intracellular Ca 2+ elevator, a sodium-potassium ATPase inhibitor, an anti-cancer chemical, a protein synthesis inhibitor, an antimicrobial, an anti-parasitic, YAP/TAZ inhibitor, a macrolide antibiotic, an anthracycline antibiotic, a topoisomerease inhibitor, a diterpenoid epoxide, a tryptamin, and an antiarythmic, and the first therapeutic and the second therapeutic are therapeutic through functioning via different biochemical pathways.
  • one of the first therapeutic and the second therapeutic are one of digitoxigenin, digoxin, strophantine octahydrate, lanatoside C, helveticoside, strophanthidin, digoxigenin, proscillaridin a, doxorubicin hydrochloride, daunorubicin hydrochloride, camptothecine, azacytidine-5, lycorine hydrochloride, cycloheximide, methyl benzethonium chloride, ivermectin, emetine dihydrochloride, pyrvinium pamoate, oleandomycin phosphate, topotecan, irinotecan, etoposide, idaruicin, doxorubicin, epiruicin, triptolide, nonyloxytrytamin, and amdiodarone, or pharmacologically acceptable salts, solvates, esters, amide
  • the disclosed invention also relates to therapeutic methods and products comprising a first pharmaceutically active agent being one of a one of an intracellular Ca 2+ elevator, a YAP / TAZ inhibitor, both a intracellular Ca 2+ elevator and a YAP / TAZ inhibitor, or pharmacologically acceptable salts, solvates, esters, amides, clathrates, stereoisomers, enantiomers, prodrugs or analogs thereof, or a combination thereof, and a second pharmaceutically active agent being one of an one of intracellular Ca 2+ elevator, a YAP / TAZ inhibitor, both a intracellular Ca 2+ elevator and a YAP / TAZ inhibitor, or pharmacologically acceptable salts, solvates, esters, amides, clathrates, stereoisomers, enantiomers, prodrugs or analogs thereof, or a combination thereof, wherein the first pharmaceutically active agent is chemically distinct from the second pharmaceutically active agent.
  • This invention also relates to pharmaceuticals that can be used therapeutically to prevent or reverse an activated fibroblast phenotype and pathologies that are a result of and/or exacerbated by hyperactive fibroblasts; and laboratory method for screening and identifying such drugs.
  • This invention also relates to the screen methodology used to discover the therapeutic drugs disclosed, including the method of identifying drugs to prevent induction of the activated fibroblast phenotype and utilizing automated immunofluorescence imagining and quantification.
  • Activated fibroblast phenotype include fibroblasts that exhibit increased proliferation or defective apoptosis, and/or enhanced contractility, elevated expression of extracellular matrix components including, but not limited to, fibronectin, Type I, III, IV, and V collagen, tenascin C, Periostin, laminins, proteoglycans, and glycoproteins, and/or elevated expression of myofibroblast protein markers including smooth muscle actin, vimentin, TAZ, PDGFR ⁇ and FAP; and/or reduced expression of FSP1 ; elevated secretion VEGFA, HGF, EGF, IGF, PDGF, TNF, IFN ⁇ , SDF1, IL-6, IL-8, PGE 2 , CTGF, CXCL7, MMPs, IL-4, IL-10, TGF ⁇ , CCL2, CCL5, CXCL9, CXCL10, nitric oxide; and/or driven by cell signaling pathways activated by Wnt ligands, TGF- ⁇ ,
  • Activated fibroblast may include at least the distinct fibroblast cell types of fibrocytes, myofibroblasts, hepatic stellate cells, pancreatic stellate cells, chollagenoblast, desmocyte.
  • pathologies including but not limited to: fibrosis, pulmonary fibrosis, Cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, cardiac fibrosis, atrial fibrosis, endomycocardial fibrosis, old myocardial fibriosis, glial scarring (gliosis), renal fibrosis, pancreatic cancer, arthrofibrosis, crohn's disease, dupuytren's contracture, myofibroblastic tumors, mediastinal fibrosis, retroperitoneal cavity fibrosis, myelofibrosis, keloid/skin fibrosis, pyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma/systemic sclerosis
  • cardioglycosides to those listed in Table 1, that are arguably therapeutic include Ouabain/Strophanthin, Deslanoside, and Lanatoside A.
  • additional therapeutic chemicals are believed to be those that activate CAMKII, and/or prevent translocation of SMAD.
  • additional therapeutic chemicals are believed to be those that activate casein kinase 1 and/or promotes degradation of TAZ.
  • components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components.
  • the defined steps can be carried out in any order or simultaneously (except where the context excludes that possibility), and the method can include one or more other steps which are carried out before any of the defined steps, between two of the defined steps, or after all the defined steps (except where the context excludes that possibility).
  • At least followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined). For example “at least 1” means 1 or more than 1.
  • at most followed by a number is used herein to denote the end of a range ending with that number (which may be a range having 1 or 0 as its lower limit, or a range having no lower limit, depending upon the variable being defined). For example, “at most 4" means 4 or less than 4, and "at most 40%” means 40% or less than 40%.
  • a range is given as "(a first number) to (a second number)" or "(a first number)-(a second number),” this means a range whose lower limit is the first number and whose upper limit is the second number.
  • 25 to 100 mm means a range whose lower limit is 25 mm, and whose upper limit is 100 mm.
  • FIG. 1 The WPMY-1 fibroblast cell line was derived from the peripheral zone of a histologically normal prostate and expresses low basal levels of activated myofibroblast markers, including fibronectin and alpha smooth muscle actin ( ⁇ -SMA).
  • Figures 1A and 1B demonstrate, by Western blot analysis and immunofluorescence microscopy, that TGF- ⁇ robustly induces fibronectin following an overnight incubation.
  • the high expression of fibronectin by activated fibroblasts, as well as its overexpression in cancer and fibrotic diseases makes it an excellent target for drug discovery.
  • the inventors Using TGF- ⁇ as an inducer of the fibronectin and the CAF phenotype, the inventors developed a high-content immunofluorescence (I.F.)-based screen to identify repurposed drugs capable of blocking the induction of fibronectin.
  • I.F. immunofluorescence
  • the 1280 compound Prestwick Chemical Library (Prestwick Chemical, Illkirch-Graffenstaden, France) and the NIH clinical collection (451 compounds) consists of FDA approved compounds (Prestwick) and compounds that have a history of use in clinical trials (NIH collection). All compounds were provided by the manufacturer at a concentration of 10 mM in DMSO. Cells were seeded at 7x10 3 cells per well in a 96-well plate. The following day, media was changed to serum-free DMEM for 24 hours.
  • the inventors developed an algorithm in which the Cellomics software analyzed intensity of fibronectin staining (channel 3) within a ring 6 to 12 pixels from the nucleus for at least 5 fields per well (100 cells per image field determined by the object count in channel 2). Compounds that decreased the intensity of fibronectin staining by at least 50% below levels of the positive control (TGF- ⁇ alone) and produced a response in a dose-dependent manner were selected for further study.
  • FIG. 2 An additional embodiment shown in Figure 2 outlines the "screening" feasibility experiments performed using the high content imaging platform Cellomics.
  • Panel A demonstrates that the Cellomics imaging platform can replicate the results observed by I.F. and in this set of experiments accurately depicting changes in fibronectin levels compared to a western blot analysis (Panel C).
  • the mask used to measure fluorescence is depicted in Panel B.
  • Reproducibility Z prime score greater than 0.5
  • the signal to noise was excellent (greater than 5) as depicted in panels D and E.
  • Cardiac glycosides have been shown previously to inhibit cell growth in a variety of cell types.
  • viability assays were performed on WPMY-1 cells over 48 hours in 1% FBS DMEM. These assays were performed using the IC 50 of each respective compound, as determined above. After 48 hours, ouabain, digoxin, and lanatoside C had no effect on cell viability compared to the DMSO control.
  • the cardiac glycoside with the lowest IC 50 , proscillaridin A caused decreased metabolic activity at 48 hours compared to the DMSO control ( figures 3 and 5 ). Therefore, the inventors focused subsequent experiments on digoxin, which has a very low IC 50 and has no effect on cell viability through 48 hours at these concentrations.
  • the inventors found that Digoxin, in a dose response fashion, effectively inhibited induction of fibronectin in three different fibroblast cell lines as demonstrated in Figure 6 , demonstrating the effect of this drug was not just limited to one cell line.
  • a further embodiment revealed in Figures 7C and 7D also indicates that digoxin inhibits TGF- ⁇ induced contraction of fibroblasts, further confirming that these drugs are blocking phenotypic differentiation of these cells as well as induction of gene expression induced by this growth factor. Contraction of the surrounding stroma by pancreatic CAFs (also called stellate cells) is one of the challenges for drugs to ultamitly reach tumors from the vasculature.
  • the Y axis in these two figures uses relative units where in Figure 8A the luciferace activity of TGF- ⁇ is set equal to 1 and in Figure 8B the luciferace activity of mock is set equal to 1.
  • the relative units are termed "arbitrary units" in the Figures.
  • DCB 3',4'-dichlorobenzamil hydrochloride
  • Thapsigargin inhibits the endoplasmic reticulum Ca 2+ ATPase, preventing storage of Ca 2+ in the endoplasmic reticulum, causing an accumulation in the cytoplasm.
  • Cells were treated with 2.5-10 ⁇ M of DCB or thapsigargin ⁇ TGF- ⁇ for 24 hours. The inventors found that DCB as well as thapsigargin were able to prevent TGF- ⁇ -induced fibronectin expression in a dose-dependent manner ( Fig 9A and 9B ).
  • Figs. 10A-10C in order to determine whether pyrvinium, similar to digoxin, was able to inhibit markers of TGF- ⁇ induced fibroblast activation, the inventors treated MRC-5 human fetal lung fibroblast cells with TGF- ⁇ and a dose escalation of either digoxin or pyrvinium. The inventors found that pyrvinium blocked the induction of fibronectin, YAP, TAZ, and smooth muscle actin by TGF- ⁇ . In furtherance of this, the inventors tested whether pyrvinium or digoxin were able to inhibit activation of fibroblasts by the combination of both TGF- ⁇ and FGF as this more accurately models a fibrotic condition driven by multiple growth factors.
  • both digoxin and pyrvinium are able to prevent the activated fibroblast phenotype, as shown by lower levels of fibronectin, YAP, TAZ, and smooth muscle actin.
  • the inventors treated fibroblasts with verteporfin, an agent that inhibits the transcriptional co-activator function of TAZ. Pyrvinium likely functions through degradation of TAZ.
  • the inventors demonstrate that eliminating the function of TAZ represses TGF- ⁇ induced fibronectin and smooth muscle actin expression.
  • TAZ levels are not reduced with verteporfin whereas they are with pyrvinium treatment.
  • Figs. 11A-11F in order to test whether digoxin and pyrvinium were able to block the induction of a activation fibroblast phenotype at the transcriptional level, the inventors performed quantitative real-time PCR. The inventors determined that digoxin and pyrvinium prevented the transcriptional induction of collagen 1a1, tenascin C, fibronectin, YAP and Snail downstream of TGF- ⁇ signaling and TAZ downstream of the fibroblast chemokine IL-8.
  • the data also suggests digoxin and pyrvinium block this phenotype through disparate molecular mechanisms as each exhibits a more potent effect toward different transcripts - note tenascin C (TNC) versus TAZ (WWTR1v2). Together this data indicates digoxin and pyrvinium are each able to broadly repress multiple markers of the activated fibroblast phenotype, markers whose expression has pathological consequences.
  • Figs. 12A-12D the inventors sought to determine which signaling pathways the commonly used anti-fibrotic drugs nintedanib and pirfenidone were able to inhibit in order to test whether digoxin or pyrvinium were more or equally effective.
  • nintedanib does not block induction by TGF- ⁇ , but blocks FGF signaling which potently upregulates TAZ in particular.
  • the inventors demonstrate that digoxin and pyrvinium each were able to block fibroblast activation from a combination of growth factors better than pirfenidone or nintedanib.
  • the inventors demonstrate in Figs.
  • both digoxin and pyrvinium are able to block the activated fibroblast phenotype better than nintedanib upon stimulation with the combination of TGF- ⁇ and FGF.
  • either or both of digoxin and pyrvinium can be used in combination with nintedanib and / or pirfenidone to block activation of fibroblasts.
  • fibroblasts pre-activated with TGF- ⁇ were chase treated with digoxin or pyrvinium alone or in combination, and were found to revert fibroblasts to the quiescent state after 24 hours of treatment as indicated by levels of fibronectin, TAZ, and smooth muscle actin. This data suggests digoxin and pyrvinium could be used to treat conditions driven by the hyperactivation of fibroblasts.
  • the inventors further tested the potential of combination treatment with digoxin and pyrvinium at a lower range of concentrations using a more sensitive and accurate methodology.
  • the inventors obtained quantitative analysis of fibronectin staining in fibroblasts upon treatment with TGF- ⁇ in the presence or absence of drug combinations. Fibronectin intensity values arrayed in panel B demonstrate that particular concentrations of digoxin and pyrvinium do exhibit an effect greater in combination than alone.
  • the inventors have presented experimental evidence that at least 28 drugs from at least 11 different categories of drugs/chemicals inhibit the TGB- ⁇ induction of fibronectin, a marker indicating CAF differentiation. Eight of these drugs were cardiac glycosides. Digoxin, and its related identified cardiac glycosides, apparently inhibits TGF- ⁇ -induced expression of fibronectin as well as several other markers indicative of CAF differentiation in two fibroblast cell lines. Digoxin appeared to impact SMAD and EGR1 transcriptional pathways. Digoxin inhibited a phenotypic property of fibroblasts, namely contraction. This inhibition was seen at low nanomolar concentrations, which have minimal effects on cell viability in vitro through 48 hours.
  • Fibronectin was chosen as the key marker of CAF differentiation for several reasons. Fibronectin is an extracellular matrix protein that binds receptor proteins called integrins and plays a role in wound healing, migration, and growth of cells during development. In cancer, this leads to increased tumor invasion and metastasis. Additionally, fibronectin is over-expressed in non-cancerous fibrotic diseases such as pulmonary fibrosis, cystic fibrosis, and cirrhosis. Finally, fibronectin shows the most significant upregulation of the CAF markers in response to TGF- ⁇ . These factors make fibronectin an attractive target for inhibition and for screens to discover drugs that block CAF formation, both in the context of cancer and fibrotic diseases.
  • BAPTA-AM (Glycine, N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-, bis[(acetyloxy)methyl] ester), a Ca 2+ chelator, had no effect on TGF- ⁇ -induced fibronectin expression.
  • TRPM8 transient receptor potential cation channel subfamily M member 8
  • menthol linalool (3,7-dimethylocta-1,6-dien-3-ol)
  • geraniol (( trans )-3,7-Dimethyl-2,6-octadien-1-ol)
  • hydroxy-citronellal (7-hydroxy-3,7-dimethyloctanal)
  • WS-3 N-ethyl-5-methyl-2-propan-2-ylcyclohexane-1-carboxamide
  • WS-23 N,2,3-trimethyl-2-propan-2-ylbutanamide
  • Frescolat MGA ((9-methyl-6-propan-2-yl-1,4-dioxas
  • the inventors used 3T3-J2 murine fibroblasts, which are highly resistant to cardiac glycosides compared to their human counterpart.
  • the inventors found that digoxin did not have an effect on TGF- ⁇ -induced fibronectin expression in murine fibroblasts. These results suggest that digoxin does function by targeting the Na + /K + ATPase.
  • digoxin appears to be inhibiting CAF differentiation at the level of transcription.
  • Analysis of mRNA levels by qPCR showed that TGF- ⁇ increases the transcript levels of CAF differentiation markers and that this increase is abrogated by the addition of digoxin.
  • Examination of the promoter regions showed that each of the CAF differentiation markers has a binding site for the TGF- ⁇ -regulated transcription factors Smad2/3 and EGR1, both of which are expressed in WPMY-1 fibroblasts.
  • Calcium-sensing receptor (CaSR) has been shown to negatively regulate Smad2 phosphorylation in response to calcium. The inventors' data evidences that digoxin prevents activity of the transcription factors Smad2/3.
  • Smad2/3 is part of a transcription factor complex that is activated in response to TGF- ⁇ signaling. Signaling through the TGF- ⁇ receptor induces phosphorylation of Smad2 and Smad3, which are free to translocate to the nucleus and form complexes with Smad4. This complex binds to promoters that regulate proliferation, apoptosis, or differentiation, depending on the cellular context.
  • Digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation, and atrial flutters. These effects were dependent on the Na + /K + ATPase. There is no previous report of the efficacy of digoxin and other cardiac in preventing the differentiation of fibroblasts to CAFs. The ability of digoxin to prevent growth factor induced fibronectin expression evidences that these compounds will be able to counteract an established disease state driven by an activated myofibroblast or CAF phenotype. Based on the above data, a pharmacologically effective dose of digoxin for a human would preferably be 0.1 to 5 mg/kg, more preferably be 0.5 to 2.5 mg/kg, and most preferably be 1.0 to 2.0 mg/kg.
  • the inventors have provided evidence that digoxin and other cardiac glycosides are effective in preventing CAF differentiation.
  • Nine other "hits" remain to be tested for their mechanism of action.
  • digoxin prevents fibroblast activation through modulation cytosolic Ca 2+ levels which leads to a decrease in the transcription of several markers of CAF differentiation.
  • the inventors evidence that digoxin/cardiac glycosides as well as the other non-cardiac glycoside drugs and other drugs and drug classes listed in Tables 1 and 2 are beneficial in combination with each other and/or with other anti-tumor agents, thus targeting the tumor epithelia as well as preventing and reversing the activation of CAFs in the tumor microenvironment.
  • Embodiments of the invention can also be: A method of treating an activated fibroblast associated disease or pre-disease condition in a mammal comprising:
  • the first therapeutic includes an intracellular Ca 2+ elevator or a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, or a combination thereof
  • the intracellular Ca 2+ elevator inhibits preferably sodium-potassium ATPase
  • the intracellular Ca 2+ elevator is a cardiaoglycoside or is selected from a group comprising menthol, linalool (3,7-dimethylocta-1,6-dien-3-ol), geraniol (( trans )-3,7-Dimethyl-2,6-octadien-1-ol), hydroxy-citronellal (7-hydroxy-3,7-dimethyloctanal), WS-3 (N-ethyl-5-methyl-2-propan-2-ylcyclohexane-1-carboxamide), WS-23 (N,2,3-trimethyl-2-
  • the first therapeutic includes a YAP / TAZ inhibitor or a pharmacologically acceptable salt, solvate, ester, amide, clathrate, stereoisomer, enantiomer, prodrug or analog thereof, or a combination thereof.
  • the YAP/TAZ inhibitor can be one of ⁇ E-catenin, thiazovivin, cucurbitacin I, dasatinib, fluvastatin, pazopanib, a statin, and pyrvinium.
  • the YAP/TAZ inhibitor can be pyrvinium prepared with a variable counter anion, the variable counter ion being one of a halide, tosylate, triflate and pamoate.
  • the pharmaceutical composition further can include a therapeutically effective amount of a second therapeutic, wherein the second therapeutic is chemically distinct from the first therapeutic.
  • the second therapeutic can be one of an intracellular Ca 2+ elevator, a YAP / TAZ inhibitor, both a intracellular Ca 2+ elevator and a YAP / TAZ inhibitor, or pharmacologically acceptable salts, solvates, esters, amides, clathrates, stereoisomers, enantiomers, prodrugs or analogs thereof, or a combination thereof or one of gemcitabine, Nab-paclitaxel, and both gemcitabine and Nab-paclitaxel or one of nintedanib, pirfenidone, and both nintedanib and pirfenidone
  • the second therapeutic can also be one of a cardioglycoside, an intracellular Ca 2+ elevator, a sodium-potassium ATPase inhibitor, an anti-cancer chemical, a protein synthesis inhibitor, an antimicrobial, an anti-parasitic, YAP/TAZ inhibitor, a macrolide antibiotic, an anthracycline antibiotic, a topoisomerease inhibitor, a diterpenoid epoxide, a tryptamin, and an antiarythmic, and wherein the activated fibroblast associated disease or pre-disease condition is one of fibrosis, pulmonary fibrosis, Cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, cardiac fibrosis, atrial fibrosis, endomycocardial fibrosis, old myocardial fibriosis,

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
EP21198646.8A 2016-02-02 2017-02-02 Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose Withdrawn EP3960181A3 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201662290002P 2016-02-02 2016-02-02
EP17748126.4A EP3411045A4 (de) 2016-02-02 2017-02-02 Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose
PCT/US2017/016160 WO2017136515A1 (en) 2016-02-02 2017-02-02 Chemicals and methods to prevent and treat tgf-beta mediated activation of fibroblasts to reduce and treat cancer and fibrosis

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP17748126.4A Division EP3411045A4 (de) 2016-02-02 2017-02-02 Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose

Publications (2)

Publication Number Publication Date
EP3960181A2 true EP3960181A2 (de) 2022-03-02
EP3960181A3 EP3960181A3 (de) 2022-06-01

Family

ID=59501045

Family Applications (2)

Application Number Title Priority Date Filing Date
EP17748126.4A Withdrawn EP3411045A4 (de) 2016-02-02 2017-02-02 Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose
EP21198646.8A Withdrawn EP3960181A3 (de) 2016-02-02 2017-02-02 Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP17748126.4A Withdrawn EP3411045A4 (de) 2016-02-02 2017-02-02 Chemikalien und verfahren zur verhinderung und behandlung von tgf-beta-vermittelter aktivierung von fibroblasten zur reduzierung und behandlung von krebs und fibrose

Country Status (3)

Country Link
US (1) US11096952B2 (de)
EP (2) EP3411045A4 (de)
WO (1) WO2017136515A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018141678A1 (en) * 2017-01-31 2018-08-09 Medizinische Hochschule Hannover (Mhh) Natural compounds and fibrosis
US10933061B2 (en) 2017-12-21 2021-03-02 Shepherd Therapeutics, Inc. Pyrvinium pamoate therapies and methods of use
US20200085784A1 (en) * 2018-09-13 2020-03-19 Minneamrita Therapeutics, LLC Methods to treat fibrosis, nash, and nafld
WO2021054978A1 (en) * 2019-09-20 2021-03-25 Pollard Bette Silver Cardiac cardenolides to reduce fibrosis and enhance epithelial differentiation
CN113244395A (zh) * 2020-02-10 2021-08-13 广州市妇女儿童医疗中心 纤维化疾病机制及其治疗药物
CN114010637A (zh) * 2021-12-06 2022-02-08 山东中医药大学 喜树碱在治疗肺纤维化中的应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1513403B1 (de) * 2002-05-28 2017-02-15 Bette Pollard Herzglykoside für die behandlung von mukoviszidose und anderen il-8-bedingten erkrankungen
US20080113042A1 (en) * 2006-09-05 2008-05-15 Chu Kee Hung Pharmaceutical composition and method for cancer treatment based on combinational use of conventional anticancer agents and geranium oil or compounds thereof
WO2008150845A1 (en) * 2007-05-31 2008-12-11 Vanderbilt University Screening for wnt pathway modulators and pyrvinium for the treatment of cance
MA40687A (fr) * 2014-04-10 2017-03-28 Ifom Fondazione St Firc Di Oncologia Molecolare Méthodes et compositions de traitement de malformation vasculaire

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"American Academy of Pediatrics: Alternative Routes of Drug Administration---Advantages and Disadvantages (Subject Review", PEDIATRICS, vol. 100, no. 1, 1997, pages 143 - 152
"Encyclopedia of Pharmaceutical Technology", vol. 5-6, 2000
"Handbook of Pharmaceutical Excipients", 2009, PHARMACEUTICAL PRESS
"The Science and Practice of Pharmacy", 2005, LIPPENCOTT WILLIAMS & WILKINS
HARRIS ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 81, no. 1, 1992, pages 1 - 10

Also Published As

Publication number Publication date
US11096952B2 (en) 2021-08-24
WO2017136515A1 (en) 2017-08-10
US20190038655A1 (en) 2019-02-07
EP3411045A4 (de) 2020-01-08
EP3411045A1 (de) 2018-12-12
EP3960181A3 (de) 2022-06-01

Similar Documents

Publication Publication Date Title
US11096952B2 (en) Chemicals and methods to prevent and treat TGF-beta mediated activation of fibroblasts to reduce and treat cancer and fibrosis
US20140030249A1 (en) Pharmaceutical Compositions
CN114010611A (zh) Jak1抑制剂的持续释放剂型
US11744827B2 (en) Cancer treatment via repositioned tricyclic anti-depressant-like drugs as anti-cancer agents and new combinations of such drugs
TWI793165B (zh) 製造及使用因多昔芬(endoxifen)之方法
EP2464340A2 (de) Pharmazeutische zusammensetzungen mit tetrabenazin
US20080199518A1 (en) Controlled-release formulation of piperazine-piperidine antagonists and agonists of the 5-HT1A receptor having enhanced intestinal dissolution
US20120208773A1 (en) Pharmaceutical compositions with tetrabenazine
KR20140129164A (ko) 히스톤 데아세틸라아제 억제제 및 파조파닙의 조합물 및 이의 용도
JP2022180531A (ja) 複素環化合物を含有する経口医薬組成物
JP2019519573A (ja) がんを処置するための方法
US10980765B2 (en) Isothiocyanatostilbenes as a novel method and product for treating cancer
WO2019055493A1 (en) METHODS AND CHEMICAL SUBSTANCES FOR TREATMENT OF MEK-RELATED PATHOLOGIES
US20170281728A1 (en) Method for treating cancer using tetradrine
CN111995629B (zh) 大根香叶衍生物及其药物组合物和其在医药中的用途
WO2009110415A1 (ja) 併用剤
US20230348470A1 (en) Gut-targeted phosphodiesterase inhibitors
WO2023158715A1 (en) Oxphos inhibitors for use in treating cancer
US20210121518A1 (en) Her2-targeted peptidomimetics grafted onto multicyclic peptide scaffolds and methods and uses
US20190328690A1 (en) Methods for treating c-met-dependent cancers
WO2018213824A2 (en) Therapeutics and methods to treat angiogenesis related pathologies

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20211020

AC Divisional application: reference to earlier application

Ref document number: 3411045

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/7048 20060101AFI20220428BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20230816

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20231129